For the first time, we have characterized mature human B cells that have an anergic phenotype, providing a critical link to twenty years of research in mice. These IgM-Low naive B cells are predominantly autoreactive and they have a reduced capacity to flux calcium, phosphorylate tyrosines or survive after stimulation. Intense stimulation causes these cells to be activated, consistent with the long-standing view that anergic B cells may be a source of pathological autoantibodies in diseases such as systemic lupus erythematosus. The long term goal of the experiments proposed herein is to translate our new basic understanding of a central mechanism of immune tolerance in humans, anergy, into a new thinking that will lead to tangible treatments of lupus. We suspect there are defects in anergic B cells that may be typical in various lupus patients, each of which could substantially alter our understanding and treatment strategies of this disease. We hypothesize that anergy is not induced or maintained for autoreactive B cells in SLE patients, allowing these cells to become fully functional. Anergic B cells may be a pool of autoreactive B cells that produce pathological autoimmune responses. To test these hypotheses in Specific aim 1, we will use flow cytometry and molecular variable gene analysis to compare the frequency and phenotype of anergic B cells in a cohort of lupus patients with age and sex matched unaffected controls.
In specific aim 2 we will determine if anergic B cells in lupus patients have altered function and the molecules involved, leading to full immune reactivity despite being autoreactive.
In specific Aim 3 we will compare the specificities and affinities of a panel of recombinant human monoclonal antibodies from anergic B cells of lupus patients to antibodies from healthy controls. With this analysis we will identify natural autoantigens that may escape tolerance and cause pathology in SLE patients.

Public Health Relevance

This study will provide an understanding of how dangerous B cells that react with our own tissues are controlled in lupus patients. The understanding of these mechanisms and exploration of how these cells are naturally controlled could provide new options for the treatment of lupus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082724-05
Application #
8477115
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$168,159
Indirect Cost
$60,365
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Liarski, Vladimir M; Kaverina, Natalya; Chang, Anthony et al. (2014) Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue. Sci Transl Med 6:230ra46
Steinsbø, Øyvind; Henry Dunand, Carole J; Huang, Min et al. (2014) Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells. Nat Commun 5:4041
Chang, Anthony; Ko, Kichul; Clark, Marcus R (2014) The emerging role of the inflammasome in kidney diseases. Curr Opin Nephrol Hypertens 23:204-10
Kinloch, Andrew J; Chang, Anthony; Ko, Kichul et al. (2014) Vimentin is a dominant target of in situ humoral immunity in human lupus tubulointerstitial nephritis. Arthritis Rheumatol 66:3359-70
Iversen, Rasmus; Di Niro, Roberto; Stamnaes, Jorunn et al. (2013) Transglutaminase 2-specific autoantibodies in celiac disease target clustered, N-terminal epitopes not displayed on the surface of cells. J Immunol 190:5981-91
Andrews, Sarah F; Zhang, Qingzhao; Lim, Samuel et al. (2013) Global analysis of B cell selection using an immunoglobulin light chain-mediated model of autoreactivity. J Exp Med 210:125-42
Di Niro, Roberto; Mesin, Luka; Zheng, Nai-Ying et al. (2012) High abundance of plasma cells secreting transglutaminase 2-specific IgA autoantibodies with limited somatic hypermutation in celiac disease intestinal lesions. Nat Med 18:441-5
Hsieh, Christine; Chang, Anthony; Brandt, Daniel et al. (2011) Predicting outcomes of lupus nephritis with tubulointerstitial inflammation and scarring. Arthritis Care Res (Hoboken) 63:865-74
Chang, Anthony; Henderson, Scott G; Brandt, Daniel et al. (2011) In situ B cell-mediated immune responses and tubulointerstitial inflammation in human lupus nephritis. J Immunol 186:1849-60
Kaur, Kaval; Sullivan, Meghan; Wilson, Patrick C (2011) Targeting B cell responses in universal influenza vaccine design. Trends Immunol 32:524-31

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